Anticoagulants are substances that prevent blood from clotting. They are commonly used during percutaneous coronary intervention (“PCI”) and other catherization techniques in order to reduce bleeding complications during surgery. One class of anticoagulants is direct thrombin inhibitors that disrupt the activity of thrombin, a serine protease involved in the coagulation cascade that initiates clotting when fibrinogen is converted to fibrin. Thrombin also activates Factor XIII into Factor XIIIa (the latter which links fibrin polymers covalently), Factors V and VIII (which promote thrombin generation), and platelets (which help propagate the thrombus).
Bivalirudin directly inhibits thrombin by specifically binding to both its catalytic site and anion-binding exosite, and is regarded as a highly effective anticoagulant for use during catherization procedures. Bivalirudin, also known as hirulog, is a synthetic congener of the naturally occurring thrombin peptide inhibitor hirudin, which is found in the saliva of the medicinal leech Hirudo medicinalis. Hirudin consists of 65 amino acids, although shorter peptide segments have proven to be effective as thrombin inhibitors. U.S. Pat. No. 5,196,404 (“'404 patent”, incorporated herein by reference) discloses bivalirudin among these shorter peptides that demonstrate anticoagulant activity. However, in contrast to hirudin, bivalirudin is a reversible thrombin inhibitor that is ideal for temporary prevention of blood clotting during catherization procedures.
Bivalirudin is a synthetic 20 amino acid peptide having the chemical name of D-Phenylalanyl-L-Prolyl-L-Arginyl-L-Prolyl-Glycyl-Glycyl-Glycyl-Glycyl-L-Asparagyl-Glycyl-L-Aspartyl-L-Phenylalanyl-L-Glutamyl-L-Glutamyl-L-Isoleucyl-L-Prolyl-L-Glutamyl-L-Glutamyl-L-Tyrosyl-L-Leucine trifluoroacetate (salt) hydrate and has a molecular weight of 2180 daltons (as the free base form). Bivalirudin is made up of the amino acid sequence: (D-Phe)-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu (SEQ ID NO: 1). As used herein, the term bivalirudin refers to the peptide comprising SEQ ID NO: 1, and salts thereof.
Bivalirudin can be formulated into a lyophilized drug product such as ANGIOMAX®. Approved indications for ANGIOMAX® include treatment in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (“PTCA”); administration with the provisional use of glycoprotein IIb/IIIa inhibitor for use as an anticoagulant in patients undergoing PCI; and treatment in patients with, or at risk of, heparin-induced thrombocytopenia (“HIT”) or heparin-induced thrombocytopenia and thrombosis syndrome (“HITTS”) undergoing PCI. See ANGIOMAX® Prescribing Information.
At present, bivalirudin is solely available in the form of a lyophilized composition that must be reconstituted prior to administration. In general, to administer a lyophilized drug composition, multiple steps are required as the lyophilized cake is first reconstituted, diluted and then administered. In some cases with certain drugs, the complete dissolution of the powder may require prolonged shaking. Lack of complete dissolution of certain drug powders can result in suboptimal dosing to the patient, which may result in decreased efficacy. Moreover, reconstitution introduces the potential for calculation and dilution errors. See generally Fanikos et al., Am. J. Cardio., 94 (2004) 532-535.
Other drugs that are marketed as RTU products are readily available for patient administration and do not require lengthy preparation. As such, these products lead to more efficient use of hospital resources and fewer mixing mistakes and dosing errors. See generally Joint Commission, 2009 National Patient Safety Goals Manual Chapter; Joint Commission, Sentinel Event Alert Issue 41, Sep. 24, 2008, Preventing Errors Relating to Commonly Used Anticoagulants. These RTU compositions give the physicians and clinicians assurance of the appropriate drug concentration, allowing them to focus on the treatment without concern for the logistics around drug preparation. Thus, patients with cardiovascular disease, who require an immediate invasive intervention, would benefit from an RTU bivalirudin composition.